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Departments of Endocrinology, Clinical Biochemistry (L.A.P.), Intensive Care (C.J.H.), Pathology (D.G.L.), and Diagnostic Imaging (R.H.R.), St. Bartholomew’s Hospital, London, United Kingdom EC1A 7BE
Address all correspondence and requests for reprints to: Dr. W. M. Drake, Department of Endocrinology, St. Bartholomew’s Hospital, West Smithfield, London, United Kingdom EC1A 7BE. E-mail: w.m.drake{at}mds.qmw.ac.uk
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Abstract |
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 Top Abstract IntroductionCase ReportMaterials and MethodsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionCase ReportMaterials and MethodsDiscussionReferences |
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Case Report |
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TopAbstractIntroductionCase ReportMaterials and MethodsDiscussionReferences |
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A year later he developed severe abdominal pain sufficient to require hospitalization, at which time he was noted be Cushingoid. He was transferred to this hospital. On examination he was obviously Cushingoid, with thin skin, moon facies, and marked proximal myopathy. The spleen was palpable 4 cm below the costal margin, but there was no hepatomegaly or lymphadenopathy.
Investigations revealed a serum potassium level of 3.1 mmol/L and a bicarbonate level of 18 mmol/L, but electrolytes and liver function tests were otherwise normal. Cushing’s syndrome was proved by loss of circadian variation of serum cortisol, a detectable sleeping midnight serum cortisol level, and lack of suppression of serum cortisol after dexamethasone administration (0.5 or 2 mg, every 6 h for 48 h). The mean serum cortisol level (calculated from the average of five samples taken through the day) was 1442 nmol/L (52.2 µg/dL). There was no rise in either serum cortisol or ACTH after iv injection of 100 µg human CRH or 10 µg desmopressin (3). A diagnosis of ectopic ACTH syndrome was made.
Computed tomography and magnetic resonance imaging scanning showed a 7 x 6-cm enhancing mass lesion in the tail of the pancreas, encasing the splenic artery and obliterating the splenic vein. Gastric rugal thickening, bilateral smooth adrenal hyperplasia, and a large perirenal pancreatic pseudocyst were noted.
Oral ketoconazole (200 mg, every 8 h) and later, in addition, metyrapone 250 mg, every 8 h) were started to control circulating cortisol levels before pancreatic surgery. During weekend leave the patient ate a restaurant meal and 2 days later, became unwell with fever and tachycardia. Salmonella enteritidis was grown from blood cultures. Parenteral antibiotics were started, but he developed peritonitis. At laparotomy a ruptured infected pancreatic pseudocyst and perforation of the third part of the duodenum were noted and repaired. He was transferred to the intensive care unit, where he spent 58 days. All oral medication, including ketoconazole and metyrapone, had to be stopped. Recurrent intraabdominal abscesses were drained under ultrasound guidance and treated with antibiotics according to laboratory sensitivity studies. Upper gastrointestinal hemorrhage necessitated repeated transfusions of blood and fresh frozen plasma. High dose omeprazole (80 mg daily) was given iv. Octreotide (600 µg daily) was administered by continuous sc infusion to inhibit pancreatic exocrine and endocrine secretion. GH (24 U daily) was given for its anabolic effects. Mean serum cortisol levels at this time were around 1200 nmol/L.
Endogenous cortisol secretion, which had been uninfluenced by
octreotide, was completely inhibited with a low dose iv etomidate
infusion (2.5 mg/h). Steroid replacement was given, initially with im
dexamethasone (to allow endogenous cortisol levels to be monitored) and
subsequently with a continuous iv hydrocortisone infusion (1–3 mg/h;
Fig. 1
). After 6 days the dose of
etomidate was reduced to 1.2 mg/h, with no increase in serum cortisol
levels. This regimen and response were continued for the 8 weeks that
he spent on artificial ventilation. Subsequently, etomidate was
discontinued, and enteral nutrition and oral medication recommenced, as
before.
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Materials and Methods |
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TopAbstractIntroductionCase ReportMaterials and MethodsDiscussionReferences |
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-hydroxyprogesterone levels were measured
using in-house RIAs (the latter requiring an initial ether extraction
step) (4, 5). Plasma ACTH was quantitated using an in-house RIA after
an initial extraction process (6). Serum dehydroepiandrosterone sulfate
(DHEAS) levels were measured using a RIA kit purchased from Hammersmith
Hospital (London, UK). Plasma gastrin samples were assayed at the
supraregional service laboratory at Hammersmith Hospital. |
Discussion |
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TopAbstractIntroductionCase ReportMaterials and MethodsDiscussionReferences |
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Etomidate and ketoconazole are members of the imidazole family of
drugs. The observation that patients in intensive care receiving long
term sedation with etomidate had increased mortality compared to other
anesthetic agents (10) was later shown to be associated with low serum
cortisol levels (11). Subsequent reports documented blunting of the
cortisol response to ACTH in vivo (7, 12) and inhibition of
ACTH-stimulated cortisol secretion from dispersed adrenal cells
in vitro (13) by etomidate, suggesting a direct effect on
the adrenal cortex rather than an inhibition of ACTH secretion. Studies
using dispersed guinea pig adrenal cells (14) suggested that etomidate
inhibits four cytochrome P450- dependent enzymes involved in
corticosteroidogenesis, although the relative importance of each of
these steps in vivo is not clear. Previous reports have
documented a rise, compared with control values, in 11-deoxycortisol
and 11-deoxycorticosterone after the administration of etomidate for
the induction of anesthesia, suggesting inhibition of
11ß-hydroxylation of both glucocorticoid and mineralocorticoid
precursors (15). Levels of progesterone and
17-hydroxyprogesterone were unchanged from control values. Similar
results are seen in dogs given etomidate when dramatic rises in ACTH
and renin are provoked by acute hemorrhage (16). In our patient, by 3
days after the commencement of etomidate, levels of 11-deoxycortisol
had fallen (Table 1), but were still above normal.
However, by this time levels of 17-hydroxyprogesterone and DHEAS had
fallen to subnormal levels, but cortisol had become undetectable. These
data would suggest that the major immediate site of action of etomidate
in our patient was earlier than previously reported, proximal to
17-hydroxylase. An additional, partial, delayed, inhibitory action
of etomidate on 11ß-hydroxylase is also indicated, as
11-deoxycortisol levels continued to fall slowly over the next 5 days.
It is possible that the onset of inhibition of 11ß-hydroxylase is
faster than that of other cytochrome P450-dependent enzymes, leading to
a rapid fall in cortisol and consistent with the rise in
11-deoxycortisol levels reported when anesthesia is induced with
etomidate in normal subjects. With more prolonged use, inhibition of
enzymatic steps more proximal in the corticosteroidogenic pathway
appears to become more important, leading to a progressive fall in
11-deoxycortisol, 17-hydroxyprogesterone and DHEAS levels.
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Since this case we have used iv etomidate as an emergency drug to control hypercortisolemia in two other patients, both with pituitary-dependent disease (Cushing’s disease). Serum cortisol levels were lowered usefully by etomidate, but, unlike the present case, in neither patient was endogenous corticosteroidogenesis completely abolished. It may be that etomidate is most effective either when the ACTH drive is fixed (as in the ectopic ACTH syndrome) or in ACTH-independent disease, so that the ability of the pituitary to reset its feedback loop makes etomidate less effective in controlling hypercortisolemia secondary to Cushing’s disease.
In summary, this patient with severe Cushing’s syndrome due to a pancreatic islet cell tumor secreting ACTH and gastrin survived peritonitis secondary to intestinal perforation and rupture of a pancreatic pseudocyst. We believe this to be due to the ability to inhibit completely excessive endogenous cortisol production with subhypnotic doses of etomidate. A serum cortisol level appropriate to the intensive care unit setting was achieved with a continuous hydrocortisone infusion. We wish to alert clinicians to the value of etomidate in circumstances where the coexistence of Cushing’s syndrome and serious abdominal pathology precludes the use of oral adrenolytic therapy.
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Acknowledgments |
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Received February 11, 1998.
Revised June 12, 1998.
Accepted June 22, 1998.
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References |
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TopAbstractIntroductionCase ReportMaterials and MethodsDiscussionReferences |
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-hydroxyprogesterone. Scand J Clin Lab Invest. 48:513–518.[Medline]
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